Oxygen depletion devices and methods for removing oxygen from red blood cells

ABSTRACT

An oxygen depletion device. The device has a cartridge; a plurality of hollow fibers extending within the cartridge from an entrance to an exit thereof; an amount of an oxygen scavenger packed within the cartridge and contiguous to and in between the plurality of hollow fibers. The hollow fibers are adapted to receiving and conveying red blood cells. There is another embodiment of an oxygen depletion device and method for removing oxygen from red blood cells.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 13/115,532, filed May 25, 2011 (pending), which claims the benefitunder 35 U.S.C. §119(e) to U.S. application Ser. No. 12/903,057, filedon Oct. 12, 2010, which claims priority to U.S. Provisional ApplicationNo. 61/250,661, filed Oct. 12, 2009. All of the foregoing applicationsare hereby incorporated by reference in their entireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under grants awarded bythe National Institutes of Health (NIH) and the National Heart Lung andBlood Institute (NHLBI). The government has certain rights in theinvention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to devices for depleting oxygen from redblood cells to enhance storage life. The present invention relates tomethods for depleting oxygen from red blood cells.

2. Background of the Art

Adequate blood supply and the storage thereof is a problem facing everymajor hospital and health organization around the world. Often, theamount of blood supply in storage is considerably smaller than the needtherefor. This is especially true during crisis periods such as naturalcatastrophes, war and the like, when the blood supply is oftenperilously close to running out. It is at critical times such as thesethat the cry for more donations of fresh blood is often heard. However,unfortunately, even when there is no crisis period, the blood supply andthat kept in storage must be constantly monitored and replenished,because stored blood does not maintain its viability for long.

Stored blood undergoes steady deterioration which is, in part, caused byhemoglobin oxidation and degradation and adenosine triphosphate (ATP)and 2-3,biphosphoglycerate (DPG) depletion. Oxygen causes hemoglobin(Hb) carried by the red blood cells (RBCs) to convert to met-Hb, thebreakdown of which produces toxic products such as hemichrome, hemin andfree Fe³⁺. Together with the oxygen, these products catalyze theformation of hydroxyl radicals (OH.cndot.), and both the OH.cndot. andthe met-Hb breakdown products damage the red blood cell lipid membrane,the membrane skeleton, and the cell contents. As such, stored blood isconsidered unusable after 6 weeks, as determined by the relativeinability of the red blood cells to survive in the circulation of thetransfusion recipient. The depletion of DPG prevents adequate transportof oxygen to tissue thereby lowering the efficacy of transfusionimmediately after administration (levels of DPG recover once inrecipient after 8-48 hrs). In addition, these deleterious effects alsoresult in reduced overall efficacy and increased side effects oftransfusion therapy with stored blood before expiration date, butpossibly older than two weeks are used.

There is, therefore, a need to be able to deplete oxygen levels in redblood cells prior to storage on a long-term basis without the storedblood undergoing the harmful effects caused by the oxygen and hemoglobininteraction.

SUMMARY OF THE INVENTION

Accordingly, the present disclosure provides for a disposable devicethat is able to remove oxygen from red blood cells.

The present disclosure provides for an oxygen depletion device. Thedevice has a cartridge; a plurality of hollow fibers extending withinthe cartridge from an entrance to an exit thereof; an amount of anoxygen scavenger packed within the cartridge and contiguous to and inbetween the plurality of hollow fibers. The hollow fibers are adapted toreceiving and conveying red blood cells.

The present disclosure provides for an oxygen depletion device. Thedevice has a receptacle of a solid material having an inlet and anoutlet adapted to receiving and expelling a flushing gas and a pluralityof hollow fibers extending within the receptacle from an entrance to anexit thereof. The hollow fibers are adapted to receiving and conveyingred blood cells.

The present disclosure provides for a method for removing oxygen fromred blood cells. The method has the step of passing the red blood cellsthrough an oxygen device. The device has a cartridge; a plurality ofhollow fibers extending within the cartridge from an entrance to an exitthereof; and an amount of an oxygen scavenger packed within thecartridge and contiguous to and in between the plurality of hollowfibers. The hollow fibers are adapted to receiving and conveying redblood cells.

The present disclosure provides for a method for removing oxygen fromred blood cells. The method has the step of passing the red blood cellsthrough an oxygen device. The device has a receptacle of a solidmaterial having an inlet and an outlet adapted to receiving andexpelling a flushing gas; and a plurality of hollow fibers filmsextending within the receptacle from an entrance to an exit thereof. Thehollow fibers are adapted to receiving and conveying red blood cells.

The present disclosure and its features and advantages will become moreapparent from the following detailed description with reference to theaccompanying drawings.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a pre-storage oxygen depletion device of the presentinvention.

FIG. 2 a illustrates an embodiment of a depletion device that depletesoxygen from red blood cells prior to storage by a flushing inert gasaround a hollow fiber inside the assembly.

FIG. 2 b illustrates an embodiment of a depletion device that depletesoxygen from red blood cells prior to storage by a flushing inert gasaround a hollow fiber inside the assembly.

FIG. 2 c illustrates an embodiment of a depletion device that depletesoxygen from red blood cells prior to storage by a flushing inert gasaround a hollow fiber inside the assembly.

FIG. 3 a illustrates another embodiment of a depletion device thatdepletes oxygen from red blood cells prior to storage.

FIG. 3 b illustrates another embodiment of a depletion device thatdepletes oxygen from red blood cells prior to storage.

FIG. 3 c illustrates another embodiment of a depletion device thatdepletes oxygen from red blood cells prior to storage.

FIG. 4 a illustrates another embodiment of a depletion device thatdepletes oxygen from red blood cells prior to storage wherein oxygen isscavenged by scavenger materials in the core of the cylinder, surroundedby hollow fibers.

FIG. 4 b illustrates another embodiment of a depletion device thatdepletes oxygen from red blood cells prior to storage wherein oxygen isscavenged by scavenger materials in the core of the cylinder, surroundedby hollow fibers.

FIG. 4 c illustrates another embodiment of a depletion device thatdepletes oxygen from red blood cells prior to storage wherein oxygen isscavenged by scavenger materials in the core of the cylinder, surroundedby hollow fibers.

FIG. 5 a illustrates another embodiment of a depletion device thatdepletes oxygen from red blood cells wherein oxygen is scavenged byscavenger materials surrounding cylinders of hollow fibers.

FIG. 5 b illustrates another embodiment of a depletion device thatdepletes oxygen from red blood cells wherein oxygen is scavenged byscavenger materials surrounding cylinders of hollow fibers.

FIG. 5 c illustrates another embodiment of a depletion device thatdepletes oxygen from red blood cells wherein oxygen is scavenged byscavenger materials surrounding cylinders of hollow fibers.

FIG. 6 illustrates a plot of flow rate of RBC suspension per minuteversus oxygen partial pressure for the depletion devices of FIGS. 2 athrough 2 c, FIGS. 3 a through 3 c, FIGS. 4 a through 4 c and FIGS. 5 athrough 5 c.

DETAILED DESCRIPTION OF THE DISCLOSURE

Referring to FIG. 2, an oxygen depletion device (ODD) 101 contains anoxygen sorbent 110. ODD 101 is a disposable cartridge 105 containingoxygen sorbent 110 and a series of hollow fibers 115. Oxygen sorbent 110is a mixture of non-toxic inorganic and/or organic salts and ferrousiron or other materials with high reactivity toward oxygen. Oxygensorbent 110 is made from particles that have significant absorbingcapacity for O₂ (more than 5 ml O₂/g) and can maintain the inside ofcartridge 105 to less than 0.01%, which corresponds to PO₂ less than0.08 mmHg. Oxygen sorbent 110 is either free or contained in an oxygenpermeable envelope. ODD 101 of the present disclosure can depleteapproximately 100 mL of oxygen from a unit of blood.

RBCs pass through hollow porous fibers 115. Porous fibers are capable ofhigh oxygen permeability rates. Suitable materials for porous fibersinclude polyolefins, TEFLON® (polytetrafluoroethylene), polyesters,polyvinylidene fluoride (PVDF), polysulfone, and other hydrophobicpolymers as well as inorganic materials (ceramics). Oxygen depletiontakes place as RBCs pass through membrane 115. ODD provides a simplestructure having a large surface area to remove oxygen and maintainconstant flow of blood therethrough. The oxygen depletion or removal isaccomplished by irreversible reaction of ferrous ion in oxygen sorbent110 with ambient oxygen to form ferric oxide. ODD 101 does not needagitation for oxygen removal and can be manufactured easily to withstandcentrifugation as part of a blood collection system as necessary.

Referring to FIGS. 2 a through 2 c and FIGS. 3 a through 3 c, examplesof flushing depletion devices are disclosed. The depletion devicesfunction to deplete O₂ by supplying appropriate composition of flushinggas. Gases appropriate for depletion devices include, for example, Ar,He, CO₂, N₂.

FIGS. 4 a through 4 c and 5 a through 5 c, also disclose scavengingdepletion devices. Depletion takes place with the use of scavengers orsorbents and without the use of external gases. In both types ofdepletion devices however, oxygen depletion is effective to enhance DPGand ATP, respectively, prior to storage in blood storage bags.

Referring to FIGS. 2 a through 2 c, a depletion device 20 is shown.Depletion device 20 includes a plurality of fibers 25, approximately5000 in number, through which red blood cells flow. Plurality of fibers25 are surrounded by a plastic cylinder 30. Plastic cylinder 30 containsa gas inlet 35 and a gas outlet 40 through which a flushing gas or acombination of flushing gases, such as those mentioned above, aresupplied to remove oxygen from blood. Specifications for depletiondevice 20 are shown in Table 1 below.

TABLE 1 Prototype Eternal Gas External Specification Pathways GasPathways Prototype Serial Device 20 #: Fiber Type: Celgard Celgard200/150-66FPI 200/150-66FPI Number of Fibers: 5000 5000 Active Length of13 28 Fibers (cm): Fiber OD 200 200 (microns): Fiber ID 150 150(microns): Total Length of 15 30 Fibers Active Fiber 0.4084 0.8796Surface Area (m2):

Referring to FIGS. 3 a through 3 c, a depletion device 45 is shown.Depletion device 45, like device 20 of FIGS. 2 a to 2 c, includes aplurality of fibers 50, approximately 5000 in number, through which redblood cells flow. Plurality of fibers 50 are surrounded by a plasticcylinder 55. Plastic cylinder 55 contains a gas inlet 60 and a gasoutlet 65 through which a gas or a combination of gases, such as thosementioned above are supplied to remove oxygen from blood. Specificationsfor depletion device 45 are shown in Table 2 below. The active surfacearea of depletion of device 45 is twice that of device 20 because device45 is twice as long as device 20.

TABLE 2 Prototype Eternal External Specification Gas Pathways GasPathways Prototype Serial Device 45 #: Fiber Type: Celgard Celgard200/150-66FPI 200/150-66FPI Number of 5000 5000 Fibers: Active Length of13 28 Fibers (cm): Fiber OD 200 200 (microns): Fiber ID 150 150(microns): Total Length of 15 30 Fibers Active Fiber 0.4084 0.8796Surface Area (m2):

FIGS. 4 a through 4 c disclose a depletion device 70 having a core 75containing scavenging materials for O₂. Core 75 is packed by a gaspermeable film with very low liquid permeability. Hollow fibers 80 arewound around core 75, and a plastic cylinder 82 contains and envelopeshollow fibers 80. In this particular embodiment, the active surface areafor depletion is approximately 0.8796 m² as shown in Table 3 below.

TABLE 3 Center 10 Core individual Prototype 125 grams Bundles 200 gramsSpecification Sorbent Sorbent Prototype Device 70 Serial #: Fiber Type:Celgard Celgard 200/150-66FPI 200/150-66FPI Number of 5000 5000 Fibers:Active Length 13 28 of Fibers (cm): Fiber OD 200 200 (microns): Fiber ID150 150 (microns): Total Length of 15 30 Fibers Active Fiber 0.87960.8796 Surface Area (m2):

FIGS. 5 a through 5 c disclose a depletion device 85 containing fiberbundles 87 enclosed in gas permeable film with very low liquidpermeability. Fiber bundles 87 are surrounded by scavenger materials 89for O₂. Fiber bundles 87 and scavenger materials 89 are contained withina plastic cylinder 90. The active surface area for depletion isapproximately 0.8796 m² as shown in Table 4 below.

TABLE 4 Center 10 Core individual Prototype 125 grams Bundles 200 gramsSpecification Sorbent Sorbent Prototype Serial Device 85 #: Fiber Type:Celgard Celgard 200/150-66FPI 200/150-66FPI Number of 5000 5000 Fibers:Active Length 13 28 of Fibers (cm): Fiber OD 200 200 (microns): Fiber ID150 150 (microns): Total Length of 15 30 Fibers Active Fiber 0.87960.8796 Surface Area (m²):

FIG. 6 is a plot of the performance of flushing depletion devices 20 and45 and scavenging depletion devices 70 and 85. The data of FIG. 6 wasplotted using the following conditions: Hematocrit, 62% (pooled 3 unitsof pRBC), and 21° C. at various head heights to produce different flowrates. Oxygen scavenger (Multisorb Technologies, Buffalo, N.Y.) wasactivated with adding 5% and 12% w/w water vapor for device 79 anddevice 85, respectively. Data are plotted with flow rate (g RBCsuspension per min) vs. pO₂ (mmHg).

In the oxygen depletion devices disclosed herein, the hollow fibers maybe packed in any suitable configuration within the cartridge, such aslinear or longitudinal, spiral, or coil, so long as they can receive andconvey red blood cells.

FIG. 6 shows that lowest oxygen saturation is achieved using devices 45and 85. Device 45 exhibits a larger active surface area exposed to gasesalong length of fibers 50. Device 85 also has a long surface area ofexposure to scavenging materials. Device 85 has bundles 87 surrounded byscavenging materials 89. The space occupied by scavenging materials 89between bundles 87 promotes dispersion of oxygen from red blood cellscontained in fiber bundles 87, thus aiding scavenging of oxygen from redblood cells.

A further use of the depletion devices is to add back oxygen prior totransfusion by flushing with pure oxygen or air. This use is for specialcases, such as massive transfusions, where the capacity of the lung toreoxygenate transfused blood is not adequate, or sickle cell anemia.

Similarly, depletion devices can be used to obtain intermediate levelsor states of depletion of oxygen depending needs of the patient toobtain optimal levels in the transfused blood depending upon thepatients needs.

It is within the scope of the present invention to remove oxygen fromthe RBCs or to strip oxygen from the blood prior to storage in thestorage bags. An oxygen scavenger can be used to remove the oxygen fromthe RBCs prior to storage in the blood bags. As used herein, “oxygenscavenger” is a material that irreversibly binds to or combines withoxygen under the conditions of use. For example, the oxygen canchemically react with some component of the material and be convertedinto another compound. Any material where the off-rate of bound oxygenis zero can serve as an oxygen scavenger. Examples of oxygen scavengersinclude iron powders and organic compounds. The term “oxygen sorbent”may be used interchangeably herein with oxygen scavenger. For example,oxygen scavengers are provided by Multisorb Technologies (Buffalo,N.Y.). Such materials can be blended to a desired ratio to achievedesired results.

It will be appreciated that scavengers can be incorporated into storagereceptacles and bags in any known form, such as in sachets, patches,coatings, pockets, and packets.

Although the present invention describes in detail certain embodiments,it is understood that variations and modifications exist known to thoseskilled in the art that are within the invention. Accordingly, thepresent invention is intended to encompass all such alternatives,modifications and variations that are within the scope of the inventionas set forth in the disclosure.

1-7. (canceled)
 8. A method for adding oxygen to red blood cellscomprising: passing red blood cells through an oxygen addition device,wherein said device comprises: a receptacle of a solid material havingan inlet and an outlet receiving and expelling a gas; and a plurality ofhollow fibers extending within said receptacle from an entrance to anexit thereof, wherein said plurality of hollow fibers receive and conveysaid red blood cells, wherein said red blood cells are passaged withinsaid hollow fibers.
 9. The method of claim 8, wherein said red bloodcells entering said oxygen addition device are oxygen-depleted red bloodcells.
 10. The method of claim 8, wherein said gas is pure oxygen. 11.The method of claim 8, wherein said gas is air.
 12. The method of claim8, wherein said plurality of hollow fibers are formed from anoxygen-permeable material selected from the group consisting ofpolyolefin, polytetrafluoroethylene, polyester, polyvinylidene fluoride(PVDF), and polysulfone.
 13. The method of claim 8, wherein saidplurality of hollow fibers are formed from a hydrophobic polymer. 14.The method of claim 8, wherein said plurality of hollow fibers areformed from an inorganic ceramic.
 15. The method of claim 8, whereinsaid plurality of hollow fibers are configured as a linear spiral, alongitudinal spiral, or a coil.
 16. A method for preparing red bloodcells for transfusion into a subject in need thereof, comprising:passing red blood cells through an oxygen addition device andtransfusing re-oxygenated red blood cells to said subject, wherein saiddevice comprises: a receptacle of a solid material having an inlet andan outlet receiving and expelling a gas; and a plurality of hollowfibers extending within said receptacle from an entrance to an exitthereof, wherein said plurality of hollow fibers receive and convey saidred blood cells, wherein said red blood cells are passaged within saidhollow fibers.
 17. The method of claim 16, wherein said subject is apatient with inadequate lung capacity to re-oxygenate transfused blood.18. The method of claim 16, wherein said subject is a patient withsickle cell anemia.
 19. The method of claim 16, wherein said red bloodcells entering said oxygen addition device are oxygen-depleted red bloodcells.
 20. The method of claim 16, wherein said gas is pure oxygen. 21.The method of claim 16, wherein said gas is air.
 22. The method of claim16, wherein said plurality of hollow fibers are formed from anoxygen-permeable material selected from the group consisting ofpolyolefin, polytetrafluoroethylene, polyester, polyvinylidene fluoride(PVDF), and polysulfone.
 23. The method of claim 16, wherein saidplurality of hollow fibers are formed from a hydrophobic polymer. 24.The method of claim 16, wherein said plurality of hollow fibers areformed from an inorganic ceramic.
 25. The method of claim 16, whereinsaid plurality of hollow fibers are configured as a linear spiral, alongitudinal spiral, or a coil.